Seyltx Reports Promising Pre-Clinical Data on GluN2B Inhibitor for Chronic Cough

Seyltx, Inc., a clinical-stage biopharmaceutical company based in Cambridge, Massachusetts, has announced promising pre-clinical data regarding their novel therapy for refractory chronic cough (RCC). These findings will be presented at the London International Cough Symposium on July 18, 2024. The data reveals that their product candidate, a highly selective GluN2B allosteric antagonist, significantly suppresses cough in a dose-dependent manner without adversely affecting basal respiratory rates.

In the pre-clinical study, guinea pigs were administered various doses of ifenprodil, followed by exposure to aerosolized citric acid to induce coughing. Results indicated a robust reduction in cough bouts correlating with increased doses of ifenprodil. Notably, doses of 3, 10, and 30 mg/kg resulted in statistically significant reductions in cough episodes without causing respiratory depression, a common concern with other antitussive agents like codeine and baclofen.

The promising data from this study, along with previous human Phase 2a efficacy results, have solidified the foundation for Seyltx's upcoming SILINDA Phase 2b clinical trial. This trial aims to assess the efficacy, safety, and tolerability of ifenprodil in RCC patients. Seyltx plans to enroll its first patient in early 2025. The study will involve approximately 240 adult participants and include three ifenprodil dose arms (40 mg TID, 80 mg TID, 120 mg TID) alongside a placebo group. The primary endpoint is the 24-hour cough frequency, which will be measured over 12 weeks.

Seyltx's President and CEO, Dietrich A. Stephan, Ph.D., highlighted the significance of GluN2B as a key regulator of the cough reflex in the brain. He noted that ifenprodil effectively inhibits the sustained high-frequency neural firing from the lungs that triggers coughing. The successful completion of this pre-clinical study, combined with Phase 2a data, supports the dosing strategy for the forthcoming Phase 2b trial.

The design of the SILINDA trial incorporates feedback from the FDA, with the aim of maximizing the trial's success. Key exploratory efficacy endpoints include the Cough Severity using the Visual Analogue Scale (CS-VAS), the Leicester Cough Questionnaire (LCQ), and real-time longitudinal cough monitoring. Topline data from the trial are anticipated by the end of 2026.

Brendan Canning, Ph.D., a Professor of Medicine at Johns Hopkins University and member of the Seyltx Scientific Advisory Board, emphasized the potential of ifenprodil as a best-in-class treatment for RCC. He remarked on the drug's impressive cough suppression effects observed at doses below the NOAEL and without compromising overall respiration.

The GluN2B receptor, targeted by ifenprodil, is implicated in the transmission of persistent high-frequency signals from the vagal afferent neurons to brain cough centers. While non-selective NMDA receptor antagonists have demonstrated antitussive properties, they are often associated with dose-limiting adverse events due to the widespread expression of NMDA receptors. Ifenprodil’s selectivity for GluN2B reduces the likelihood of these adverse effects, making it a promising candidate for treating chronic cough.

Seyltx plans to extend the potential application of ifenprodil to other conditions involving neuronal hypersensitivity, such as cough associated with idiopathic pulmonary fibrosis (IPF). An open-label Phase 2a trial in IPF-associated cough showed a 40% reduction in cough counts and an 80% patient response rate. These findings further support ifenprodil's efficacy across different patient populations.

The company is optimistic about the future prospects of ifenprodil and is keen to collaborate with the broader clinical community. Jacky Smith, MB, ChB, FRCP, Ph.D., a Professor of Respiratory Medicine at the University of Manchester and member of the Seyltx Scientific Advisory Board, expressed confidence that the ongoing and planned clinical trials will harness recent insights to enhance the trial's chances of success and potentially provide relief to millions of RCC patients.

In summary, Seyltx's recent pre-clinical findings and upcoming clinical trial plans indicate a strong potential for their selective GluN2B antagonist, ifenprodil, to become a significant therapeutic option for patients suffering from RCC and possibly other related conditions.